The present invention relates to compounds which potentiate neurotransmission by promoting the release of neurotransmitters such as acetylcholine, dopamine and norepinephrine. More particularly, the present invention relates to compounds that are capable of modulating acetylcholine receptors. Invention compounds are useful, for example, for treatment of dysfunction of the central and autonomic nervous systems (e.g. dementia, cognitive disorders, neurodegenerative disorders, extrapyramidal disorders, convulsive disorders, cardiovascular disorders, endocrine disorders, pain, eating disorders, affective disorders, drug abuse, and the like). Invention compounds are also expected to exhibit neuroprotective effects. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as various uses therefor.
By modulating neurotransmitter release (including dopamine, norepinephrine, acetylcholine and serotonin) from different brain regions, acetylcholine receptors are involved in the modulation of neuroendocrine function, respiration, mood, motor control and function, focus and attention, concentration, memory and cognition, and the mechanisms of substance abuse. Ligands for acetylcholine receptors have been demonstrated to have effects on attention, cognition, appetite, substance abuse, memory, extrapyramidal function, cardiovascular function, pain, gastrointestinal motility and function, as well as exhibiting neuroprotective effects. The distribution of acetylcholine receptors that bind nicotine, i.e., nicotinic acetylcholine receptors, is widespread in the brain, including the basal ganglia, limbic system, cerebral cortex and mid- and hind-brain nuclei. In the periphery, the distribution includes muscle, autonomic ganglia, the gastrointestinal tract and the cardiovascular system.
Acetylcholine receptors have been shown to be decreased, inter alia, in the brains of patients suffering from Alzheimer""s disease or Parkinson""s disease, diseases associated with dementia, motor dysfunction and cognitive impairment. Such correlations between acetylcholine receptors and nervous system disorders suggest that compounds that modulate acetylcholine receptors will have beneficial therapeutic effects for many human nervous system disorders. Thus, there is a continuing need for compounds which have the ability to modulate the activity of acetylcholine receptors. In response to such need, the present invention provides a new family of compounds which modulate acetylcholine receptors.
In accordance with the present invention, we have discovered a novel class of substituted pyridine compounds (containing an ether, ester, amide, ketone or thioether functionality) that promote the release of ligands involved in neurotransmission. More particularly, compounds of the present invention are capable of modulating acetylcholine receptors.
The compounds of the present invention are capable of displacing one or more acetylcholine receptor ligands, e.g., 3H-nicotine, from mammalian neuronal membrane binding sites. In addition, invention compounds display activity in cell lines which express recombinant acetylcholine receptors. It can readily be seen, therefore, that invention compounds may act as agonists, partial agonists, antagonists or allosteric modulators of acetylcholine receptors. Therapeutic indications for compounds with activity at acetylcholine receptors include diseases of the central nervous system such as Alzheimer""s disease and other diseases involving memory loss and/or dementia (including AIDS dementia); cognitive dysfunction (including disorders of attention, focus and concentration), disorders of extrapyramidal motor function such as Parkinson""s disease, progressive supramuscular palsy, Huntington""s disease, Gilles de la Tourette syndrome and tardive dyskinesia; mood and emotional disorders such as depression, anxiety and psychosis; substance abuse including withdrawal symptoms and substitution therapy; neurocrine disorders and dysregulation of food intake, including bulimia and anorexia; disorders or nociception and control of pain; autonomic disorders including dysfunction of gastrointestinal motility and function such as inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation, gastric acid secretion and ulcers; phaeochromocytoma, cardiovascular dysfunction including hypertension and cardiac arrhythmias, as well as co-medication uses in surgical applications. Compounds with activity at acetylcholine receptors have also been shown to have neuroprotective effects.
In accordance with the present invention, there are provided methods of modulating the activity of acetylcholine receptors. As employed herein, the phrase xe2x80x9cmodulating the activity of acetylcholine receptorsxe2x80x9d refers to a variety of therapeutic applications, such as the treatment of Alzheimer""s disease and other disorders involving memory loss and/or dementia (including AIDS dementia); cognitive dysfunction (including disorders of attention, focus and concentration), disorders of extrapyramidal motor function such as Parkinson""s disease, progressive supramuscular palsy, Huntington""s disease, Gilles de la Tourette syndrome and tardive dyskinesia; mood and emotional disorders such as depression, panic, anxiety and psychosis; substance abuse including withdrawal syndromes and substitution therapy; neuroendocrine disorders and dysregulation of food intake, including bulemia and anorexia; disorders of nociception and control of pain; neuroprotection; autonomic disorders including dysfunction of gastrointestinal motility and function such as inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation, gastric acid secretion and ulcers; pheochromocytoma; cardiovascular dysfunction including hypertension and cardiac arrhythmias, comedication in surgical procedures, and the like.
The compounds of the present invention are especially useful for the treatment of Alzheimer""s disease as well as other types of dementia (including dementia associated with AIDS), Parkinson""s disease, cognitive dysfunction (including disorders of attention, focus and concentration), attention deficit syndrome, affective disorders, and for the control of pain. Thus modulation of the activity of acetylcholine receptors present on or within the cells of a patient suffering from any of the above-described indications will impart a therapeutic effect.
Invention methods comprise contacting cell-associated acetylcholine receptors with a concentration of a compound of Formula Z sufficient to modulate the activity of said acetylcholine receptors, compounds having Formula Z being defined as follows: 
or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof,
wherein:
A and B are independently selected from xe2x80x94Nxe2x80x94 or xe2x80x94Cxe2x80x94, with the proviso that one of A and B is xe2x80x94Nxe2x80x94;
each of R1, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, cyano, cyanomethyl, nitro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, heterocyclic, substituted heterocyclic, trifluoromethyl, pentafluoroethyl, xe2x80x94ORA, xe2x80x94Oxe2x80x94C(O)xe2x80x94RA, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(RA)2, xe2x80x94SRA, xe2x80x94NHC(O)RA or xe2x80x94NHSO2RA, wherein RA is selected from H, lower alkyl, substituted lower alkyl, aryl or substituted aryl, or xe2x80x94NRBRB, wherein each RB is independently selected from hydrogen or lower alkyl, such that when A is xe2x80x94Nxe2x80x94, R1 is absent and when B is xe2x80x94Nxe2x80x94, R3 is absent;
D is optionally present; and when D is present, D is selected from lower alkylene, substituted lower alkylene, cycloalkylene, substituted cycloalkylene, lower alkenylene, substituted lower alkenylene, or lower alkynylene;
E is optionally present; and when E is present, E is selected from xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NRCxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NRCxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)xe2x80x94NRCxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NRCxe2x80x94 or xe2x80x94S(O)xe2x95x90NH, wherein RC is selected from hydrogen, lower alkyl or substituted lower alkyl;
G is optionally present; and when G is present, G is selected from lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene or lower alkynylene;
J is a dialkylamino group having the structure Jxe2x80x2: 
wherein:
RE and RF are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl and cycloalkyl, or
RE and RF combine to form a 3-7 membered ring (with 4-6 membered rings being presently preferred), or
J is a nitrogen-containing cyclic moiety having the structure Jxe2x80x3: 
as well as bicyclic-derivatives thereof,
wherein:
one or both R* can cooperate with one another or with RD to form further ring(s) or when R* does not cooperate to form a ring, R* is hydrogen,
m is 0-2,
n is 0-3,
X is optionally present, and when present is selected from xe2x80x94Oxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94CH2S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CH2S(O)2xe2x80x94 or xe2x80x94CH2Nxe2x80x94, and
RD is selected from hydrogen, lower alkyl or lower cycloalkyl, or RD is absent when the nitrogen atom to which it is attached participates in the formation of a double bond,
with the proviso that when A is xe2x80x94Nxe2x80x94, B is xe2x80x94Cxe2x80x94, one of R2, R3 or R5 is Cl, D is absent, E is xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94, and G is alkylene containing 2-4 carbon atoms and J is Jxe2x80x2; or when A is xe2x80x94Nxe2x80x94, B is xe2x80x94Cxe2x80x94, D is absent, G is absent or alkylene containing 1-4 carbon atoms, and J is Jxe2x80x3, and Jxe2x80x3 is monocyclic, tropanyl or quinuclidyl, then said modulation does not embrace the control of pain.
Bicyclic derivatives of the above-described nitrogen-containing cyclic moieties include a wide variety of azabicyclic moieties, as described in greater detail herein below.
As employed herein, the phrase xe2x80x9can effective amountxe2x80x9d, when used in reference to compounds of the invention, refers to doses of compound sufficient to provide circulating concentrations high enough to impart a beneficial effect on the recipient thereof. Such levels typically fall in the range of about 0.001 up to 100 mg/kg/day; with levels in the range of about 0.05 up to 10 mg/kg/day being preferred.
As employed herein, xe2x80x9clower alkylxe2x80x9d refers to straight or branched chain alkyl radicals having in the range of about 1 up to 4 carbon atoms; xe2x80x9calkylxe2x80x9d refers to straight or branched chain alkyl radicals having in the range of about 1 up to 12 carbon atoms; xe2x80x9csubstituted alkylxe2x80x9d refers to alkyl radicals further bearing one or more substituents such as hydroxy, alkoxy (of a lower alkyl group), mercapto (of a lower alkyl group), aryl, heterocyclic, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, carboxyl, carbamate, sulfonyl, sulfonamide, and the like;
xe2x80x9clower alkylenexe2x80x9d refers to straight or branched chain alkylene radicals (i.e., divalent alkyl moieties, e.g., methylene) having in the range of about 1 up to 4 carbon atoms; xe2x80x9calkylenexe2x80x9d refers to straight or branched chain alkylene radicals having in the range of about 1 up to 12 carbon atoms; and xe2x80x9csubstituted alkylenexe2x80x9d refers to alkylene radicals further bearing one or more substituents as set forth above;
xe2x80x9clower cycloalkylxe2x80x9d refers to cyclic radicals containing 3 or 4 carbon atoms, xe2x80x9csubstituted lower cycloalkylxe2x80x9d refers to lower cycloalkyl radicals further bearing one or more substituents as set forth above, xe2x80x9ccycloalkylxe2x80x9d refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms, and xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl radicals further bearing one or more substituents as set forth above;
xe2x80x9ccycloalkylenexe2x80x9d refers to cyclic ring-containing divalent radicals containing in the range of about 3 up to 8 carbon atoms (e.g. cyclohexylene), and xe2x80x9csubstituted cycloalkylenexe2x80x9d refers to cycloalkylene radicals further bearing one or more substituents as set forth above;
xe2x80x9clower alkenylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon double bond, and having in the range of about 2 up to 4 carbon atoms, and xe2x80x9csubstituted lower alkenylxe2x80x9d refers to alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 to 6 carbon atoms presently preferred), and xe2x80x9csubstituted lower alkenylxe2x80x9d refers to alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9clower alkenylenexe2x80x9d refers to straight or branched chain alkenylene radicals (i.e., divalent alkenyl moieties, e.g., ethylidene) having at least one carbon-carbon double bond, and having in the range of about 2 up to 4 carbon atoms, and xe2x80x9csubstituted lower alkenylenexe2x80x9d refers to divalent alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkenylenexe2x80x9d refers to straight or branched chain divalent alkenyl moieties having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkenyl moieties having in the range of about 2 to 6 carbon atoms presently preferred), and xe2x80x9csubstituted lower alkenylenexe2x80x9d refers to divalent alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9clower alkynylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 4 carbon atoms, and xe2x80x9csubstituted lower alkynylxe2x80x9d refers to alkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently being preferred), and xe2x80x9csubstituted alkynylxe2x80x9d refers to alkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9clower alkynylenexe2x80x9d refers to straight or branched chain alkynylene radicals (i.e., divalent alkynyl moieties, e.g., ethynylidene) having at least one carbon-carbon triple bond, and having in the range of about 2 up to 4 carbon atoms, and xe2x80x9csubstituted lower alkynylenexe2x80x9d refers to divalent alkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkynylenexe2x80x9d refers to straight or branched chain divalent alkynyl moieties having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkynyl moieties having in the range of about 2 to 6 carbon atoms presently being preferred), and xe2x80x9csubstituted alkynylenexe2x80x9d refers to divalent alkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylxe2x80x9d refers to aromatic radicals having in the range of 6 up to 14 carbon atoms and xe2x80x9csubstituted arylxe2x80x9d refers to aryl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkylarylxe2x80x9d refers to alkyl-substituted aryl radicals and xe2x80x9csubstituted alkylarylxe2x80x9d refers to alkylaryl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylalkylxe2x80x9d refers to aryl-substituted alkyl radicals and xe2x80x9csubstituted arylalkylxe2x80x9d refers to arylalkyl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylalkenylxe2x80x9d refers to aryl-substituted alkenyl radicals and xe2x80x9csubstituted arylalkenylxe2x80x9d refers to arylalkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylalkynylxe2x80x9d refers to aryl-substituted alkynyl radicals and xe2x80x9csubstituted arylalkynylxe2x80x9d refers to arylalkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9cheterocyclicxe2x80x9d refers to cyclic (i.e., ring-containing) radicals containing one or more heteroatoms (e.g., N, O, S) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and xe2x80x9csubstituted heterocyclicxe2x80x9d refers to heterocyclic radicals further bearing one or more substituents as set forth above;
xe2x80x9cazabicyclic moietiesxe2x80x9d refers to fully saturated bicyclic species bearing a nitrogen atom at one of the ring positions, or such moieties may contain one or more sites of unsaturation. Examples of azabicyclic moieties contemplated for use in the practice of the present invention include azabicycloalkanes such as 7-azabicyclo[2.2.1]heptane, N-methyl 7-azabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, N-methyl 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, N-methyl 1-azabicyclo[2.2.2]octane, 9-azabicyclo[4.2.1]nonane, N-methyl 9-azabicyclo[4.2.1]-nonane, and the like; azabicycloalkenes such as 9-methyl-9-azabicyclo[4.2.1]non-2-ene, and the like. The stereochemistry of azabicyclic moieties includes both endo- and exo- isomers;
xe2x80x9chalogenxe2x80x9d refers to fluoride, chloride, bromide or iodide radicals.
In accordance with the present invention there are also provided compounds of formula Z as defined hereinabove, excluding compounds wherein:
A is xe2x80x94Nxe2x80x94, B is xe2x80x94Cxe2x80x94, one of R2, R3 or R5 is Cl, D is absent, E is xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94, G is alkylene containing 2-4 carbon atoms and J is Jxe2x80x2, or
A is xe2x80x94Nxe2x80x94, B is xe2x80x94Cxe2x80x94, D is absent, G is absent or alkylene containing 1-4 carbon atoms, J is Jxe2x80x3, and Jxe2x80x3 is monocyclic, tropanyl or quinuclidyl.
In accordance with the present invention, A and B are independently selected from xe2x80x94Nxe2x80x94 and xe2x80x94Cxe2x80x94 with the proviso that one of A and B is xe2x80x94Nxe2x80x94. Each of R1 through R5 are independently selected from hydrogen, halogen, cyano, cyanomethyl, nitro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, heterocyclic, substituted heterocyclic, perfluoro alkyl (such as, for example, trifluoromethyl, pentafluoroethyl, and the like), xe2x80x94ORA, xe2x80x94Oxe2x80x94C(O)xe2x80x94RA, xe2x80x94Oxe2x80x94C(O)xe2x80x94 N(RA)2, xe2x80x94SRA, xe2x80x94NHC(O)RA or xe2x80x94NHSO2RA, wherein RA is selected from H, lower alkyl, substituted lower alkyl, aryl or substituted aryl, or xe2x80x94NRBRB, wherein each RB is independently selected from hydrogen and lower alkyl.
Preferred compounds are those in which R1 through R5 are each selected from hydrogen, halogen, alkyl, substituted e alkyl (including perfluoroalkyl), alkynyl, substituted alkynyl, xe2x80x94ORA or xe2x80x94SRA, wherein RA is selected from H, lower alkyl or aryl, or xe2x80x94NRBRB, wherein each RB is independently selected from hydrogen or lower alkyl. More preferably each of R1 through R5 are independently selected from hydrogen, lower alkyl, halogen, hydroxyl, hydroxymethyl, alkoxy, amino, and the like.
In accordance with the present invention, D, when present, is selected from straight chain lower alkylene and substituted lower alkylene moieties, or cycloalkylene and substituted cycloalkylene, or lower alkenylene and substituted alkenylene moieties, or lower alkynylene moieties. It is presently preferred that D not be present, or when present, it is preferred that for D be a lower alkylene chain containing 1 to 3 carbon atoms in the backbone thereof. In particularly preferred compounds of the present invention D is absent or methylene.
Further in accordance with the present invention, E is selected from xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94C(O)NRCxe2x80x94, wherein RC is selected from hydrogen, lower alkyl or substituted lower alkyl. Preferably E is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94S(O)2xe2x80x94. It is presently especially preferred that E is selected from xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94.
Still further in accordance with the present invention, G is selected from straight chain lower alkylene and substituted lower alkylene moieties (preferably having up to 3 atoms in the backbone thereof), or lower alkenylene moieties (preferably having about 3 atoms in the backbone thereof), or substituted lower alkenylene moieties and lower alkynylene moieties (preferably having about 3 atoms in the backbone thereof). Presently preferred moieties for G are lower alkylene, of 1 to 3 carbon atoms.
Yet still further in accordance with the present invention, J is a dialkylamino group having the structure (Jxe2x80x2): 
wherein:
RE and RF are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl and cycloalkyl, or
RE and RF combine to form a 3-7 membered ring (with 4-6 membered rings being presently preferred), or
J is a nitrogen-containing cyclic moiety having the structure(Jxe2x80x3): 
xe2x80x83as well as bicyclic-derivatives thereof,
wherein:
one or both R* can cooperate with one another or with RD to form further ring(s),
m is 0-2,
n is 0-3,
X is optionally present, and when present is selected from xe2x80x94Oxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94CH2S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CH2S(O)2xe2x80x94 or xe2x80x94CH2Nxe2x80x94, and
RD is selected from hydrogen, lower alkyl or lower cycloalkyl, or RD is absent when the nitrogen atom to which it is attached participates in the formation of a double bond.
Thus, for example, J can be a dialkylamino moiety, an aziridino moiety, azetidino moiety, tetrahydrooxazolo moiety, tetrahydrothiazolo moiety, pyrrolidino moiety, piperidino moiety, morpholino moiety, thiomorpholino moiety, piperazino moiety, an azabicyclic moiety, and the like. Presently preferred compounds include those wherein J is an azetidino moiety, pyrrolidino moiety, 1-methylpyrrolidino moiety, piperidine moiety; 1-methylpiperidine moiety, an azabicyclic moiety (e.g., 7-azabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, 9-azabicyclo[4.2.1]nonane, 9-methyl-9-azabicyclo[4.2.1]non-2-ene), and the like.
Preferred compounds of the present invention include those wherein A and B are independently selected from xe2x80x94Nxe2x80x94 and xe2x80x94Cxe2x80x94 with the proviso that one of A and B is xe2x80x94Nxe2x80x94, D is lower alkylene or absent; E is as previously defined; G is lower alkylene or lower alkenylene, and J forms a 4-, 5- or 6-membered heterocyclic ring or is an azabiocyclic moiety. Particularly preferred compounds of the present invention include those wherein A and B are as defined above, D is methylene or absent, E is xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94; G is methylene or ethylene; and J is pyrrolidino, 1-methylpyrrolidino, piperidino, 1-methylpiperidino or an azabicyclic moiety.
Additional preferred compounds of the present invention include those wherein E is xe2x80x94C(O)Oxe2x80x94; D is lower alkylene; G is lower alkylene; and J is pyrrolidino, 1-methylpyrrolidino, piperidino, 1-methylpiperidino or an azabicyclic moiety.
Additional preferred compounds of the invention include those wherein E is xe2x80x94Sxe2x80x94; D is not present; G is methylene or ethylene; J is pyrrolidino, 1-methylpyrrolidino, piperidino, 1-methylpiperidino or an azabicyclic moiety.
Additional preferred compounds of the invention include those wherein E is xe2x80x94Oxe2x80x94; D is methylene or not present; G is methylene; J is pyrrolidino, 1-methylpyrrolidino, piperidino, 1-methylpiperidino or an azabicyclic moiety.
Additional preferred compounds of the invention include those wherein E is xe2x80x94Sxe2x80x94; D is methylene or not present; G is methylene; and at least one of R1, R2, R3, R4 or R5 is not hydrogen.
Additional preferred compounds of the invention include those wherein E is xe2x80x94Sxe2x80x94; neither D nor G are present; J is pyrrolidino, piperidino or azabicyclic moiety; as well as compounds wherein E is xe2x80x94Sxe2x80x94; D is not present; G is methylene; and J is an azabicyclic moiety.
Additional preferred compounds of the invention include those wherein E is xe2x80x94Sxe2x80x94; D is not present; G is xe2x80x94(CH2)nxe2x80x94, wherein n=1-6, e.g., methylene, ethylene, propylene, butylene, and the like; and J is dialkylamino (e.g., dimethylamino), pyrrolidino, piperidino, or an azabicyclic moiety.
Invention compounds have affinity for acetylcholine receptors. As employed herein, the term xe2x80x9cacetylcholine receptorxe2x80x9d refers to both nicotinic and muscarinic acetylcholine receptors. Affinity of invention compounds for such receptors can be demonstrated in a variety of ways, e.g., via competitive radioligand binding experiments in which the test compounds displace isotopically labeled ligands (such as nicotine, cytisine, methylcarbamylcholine, quinuclidinyl benzilate, and the like) from binding sites in mammalian cerebral membranes (see, e.g., Example 35). Furthermore, the binding of compounds to acetylcholine receptors can be evaluated as a functional response (see, e.g., Example 37). For example, the activity of invention compounds can be evaluated employing functional assays based on recombinant neuronal acetylcholine receptor expression systems (see, for example, Williams et al., Drug News and Perspectives 7:205-223 (1994)). Test compounds can also be evaluated for their ability to modulate the release of neurotransmitters (e.g., dopamine, norepinephrine, and the like) from rat brain slices (e.g., striatum, hippocampus, and the like). See, e.g., Example 36.
Moreover, test compounds can also be evaluated by way of behavioral studies employing animal models of various CNS, autonomic and cardiovascular disorders (see, for example, D""Amour and Smith, J. Pharmacol. Exp. Ther. 72:74-79 (1941) and Iwamoto, J. Pharmacol. Exp. Ther. 251:412-421 (1989) for animal models of pain; Klockgether and Turski, Ann. Neurol. 28:539-546 (1990), Colpaert, F., Neuropharmacology 26:1431-1440 (1987), Ungerstedt and Arbuthknott, Brain Res. 24:485-493 (1970), Von Voigtlander and Moore, Neuropharmacology 12:451-462 (1973), Ungerstedt et al., Adv. Neurol. 3:257-279 (1973), Albanese et al., Neuroscience 55:823-832 (1993), Janson et al., Clin. Investig. 70:232-238 (1992), Sundstrom et al., Brain Res. 528:181-188 (1990), Sershen et al., Pharmacol. Biochem. Behav. 28:299-303 (1987) for animal models of Parkinson""s disease; Williams et al., Gastroenterology 94:611-621 (1988), Miyata et al., J. Pharmacol. Exp. Ther. 261:297-303 (1992), Yamada et al., Jpn. J. Pharmacol. 58 (Suppl.):131 (1992) for animal models of irritable bowel syndrome; Coyle et al., Neurobehav. Toxicol. Tetatol. 5:617-624 (1983), Schartz et al., Science 219:316-318 (1983) for animal models of Huntington""s disease; Clow et al., Euro. J. Pharmacol. 57:365-375 (1979), Christensen et al., Psychoparmacol. 48:1-6 (1976), Rupniak et al., Psychopharmacol. 79:226-230 (1983), Waddington et al., Science 220:530-532 (1983) for animal models of tardive dyskinesia; Emerich et al., Pharmacol. Biochem. Behav. 38:875-880 (1991) for animal models of Gilles de la Tourette""s syndrome; Brioni et al., Eur. J. Pharmacol. 238:1-8 (1993), Pellow et al., J. Neurosci. Meth. 14:149 (1985) for animal models of anxiety; and Estrella et al., Br. J. Pharmacol 93:759-768 (1988) for the rat phrenic nerve model which indicates whether a compound has muscle effects that may be useful in treating neuromuscular disorders).
Those of skill in the art recognize that invention compounds may contain one or more chiral centers, and thus can exist as racemic mixtures. For many applications, it is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions.
In the following reaction Schemes, each of A, B, D, E, G and J are as defined above. When any one or more of the R-group substituents (i.e., R1, R2, R3, R4 or R5) are xe2x80x94OH or xe2x80x94SH, it will be readily apparent to those of skill in the art that this functional group.may require the use of xe2x80x9cprotecting groupsxe2x80x9d (e.g., t-butyldimethylsilyl (t-BDMS), benzyl (Bn) or tetrahydrophenyl (THP), and the like) during the coupling reaction to xe2x80x9cblockxe2x80x9d the reactivity of the R group. Similarly, when the R-group is xe2x80x94NH2, protecting groups (e.g., 9-fluoromethylcarbonyl (FMOC), butoxycarbonyl (BOC), benzoyloxycarbonyl (CBZ), and the like) may be required. Furthermore, when J=pyrrolidine, an additional protecting step may be required. For such purpose, BOC, CBZ, and the like can be employed. Hence, subsequent deprotection will be required prior to analysis.
A variety of methods can be employed for the preparation of compounds having the general formula Z. For example, an example scheme for the production of compounds wherein E represents a sulfur linking moiety are shown in Reaction Schemes I and II. 
All variables used in the schemes presented herein are as defined above, and nxe2x80x2 and nxe2x80x3 each fall within the range of 1-3.
In reaction Scheme I the sulfhydryl derivatives, (compounds I) are commercially available (e.g., 2-mercaptopyridine, 4-mercaptopyridine, Aldrich Chemical Co., 2-pyridinemethanethiol, Pyrazine Specialties Inc.) or may readily be prepared by those skilled in the art by selecting the appropriate D moiety (e.g., 2-pyridinemethanethiol, 2-pyridineethanethiol, Barnes, J. H. et al., Eur. J. Med. Chem. 23:211 (1988)).
Alternatively, the sodium or lithium salt of I can be used to produce compounds of general Formula IVa or IVb. In this case no base is needed and the reaction can be conducted in a solvent such as methanol or ethanol. Reaction times required for this coupling procedure can vary widely and fall in the range of 10 minutes up to about 24 hours. Preferred reaction times fall in the range of about one hour. This reaction can be carried out over a wide range of temperatures. Temperatures in the range of room temperature are presently preferred.
In Reaction Scheme I, the sulfur compounds (compounds I) are effectively contacted with halides or their equivalents, especially chloride or mesylate derivatives (compounds IIa or IIb), optionally bearing G. Compounds IIa or IIb are commercially available (e.g., 2-(2-chloroethyl)-1-methylpyrrolidine, Aldrich Chemical Co.) or may be prepared from starting materials well-known to those skilled in the art (see e.g., Wrobel and Hejchman, Synthesis 5:452 (1987) or Gautier et al., Ann. Pharm. Fr. 30:715 (1972)) or, alternatively, the mesylate derivative or the chloro derivative may also be prepared from the corresponding alcohol (compound IIIa or IIIb), according, respectively, to Fxc3xcrst and Koller, Helv. Chim. Acta 30:1454 (1947) and Tabushi, I., Tetrahedron Lett. 293 (1970). The alcohol derivatives are commercially available (e.g., tropinone, Aldrich Chemical Co.), may be prepared (e.g., endo-7-methyl-7-azabicyclo[2.2.1]heptane-2-ol, Pfister, J. R. et al., J. Pharm. Sci. 74:108 (1985); endo-7-azabicyclo[2.2.1]heptane-2-ol, Fletcher,J., J. Org. Chem. 59:1771 (1994); exo or endo-9-methyl-9-azabicyclo[4.2.1]nonane, Campell, H. F. et al., Can. Pol. J. Chem. 53:27 (1979) or can be obtained by reduction of the corresponding ester using methods well-known to those skilled in the art (e.g., 6-carboxylic acid-8-methyl-8-azabicyclo[3.2.1]octane-methylester, Gonzalez at al., J. Am. Chem. 117:3405 (1995)). Similarly, chloro, mesylate or tosylate derivatives of dialkylamines can be used instead of compounds of Formula IIa or IIb. This coupling reaction is promoted by suitable base, such as, for example potassium hydroxide, sodium hydride, sodium ethoxide, potassium carbonate, 1,8-diazatribyclo[5.4.0]undec-7-ene (DBU), and the like. Presently preferred base for use in the practice of the present invention is potassium carbonate or sodium hydride. The above-described reaction is typically carried out in a solvent such as methanol, tetrahydrofuran (THF), dimethylformamide (DMF), and the like. Presently preferred solvent for use in the practice of the present invention is DMF or a 50/50 mixture of THF and DMF.
Typically the coupling reaction can be carried out over a wide range of temperatures. Temperatures in the range of room temperature to 80xc2x0 C. are presently preferred. Reaction times required to effect the desired coupling reaction can vary widely, typically falling in the range of 10 minutes up to about 24 hours. Preferred reaction times fall in the range of about 30 minutes to 12 hours. The resulting thioether derivative may be purified and analyzed by techniques well known to those skilled in the art.
Alternatively, compounds of Formula IVa or IVb may be prepared following the reaction described in Reaction Scheme II. 
In Reaction Scheme II, compound of formula V (wherein D is selected from methylene or ethylene unit and Yxe2x80x2 is halogen, a mesylate or a tosylate group) are commercially available or may be readily prepared from starting materials well-known to those skilled in the art. Compounds VIa or VIb can be prepared according to Reaction Scheme III from the corresponding compound of general formula IIa or IIb. When Yxe2x80x3 is hydrogen, the coupling reaction is promoted by suitable base, such as, for example potassium hydroxide, sodium hydride, sodium ethoxide, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like. Presently preferred base for use in the practice of the present invention is potassium carbonate or sodium hydride.
The above-described reaction is typically carried out in a solvent such as methanol, THF, DMF, and the like. Presently preferred solvent for use in the practice of the present invention is DMF or a 50/50 mixture of THF and DMF.
When Yxe2x80x3 is a sodium or lithium cation, the coupling reaction is conducted directly after the hydrolysis of the thioacetate (Scheme III) in the same solvent (methanol) in a one pot reaction by addition of one equivalent of compound of general Formula V.
A method for the preparation of compounds of general Formula VIa or VIb is depicted in Scheme III. 
In Step A of reaction Scheme III, compound of general formula IIa or IIb is contacted with potassium thioacetate, via a nucleophilic substitution well known to those skilled in the art in order to obtain the thioacetate of general Formula VIIa or VIIb.
In Step B of the reaction Scheme III, the resulting thioesters (compound VIIa or VIIb) are hydrolyzed using procedures well know to those of skill in the art, such as litium hydroxide in methanol, sodium methoxide in methanol and the like, to provide the desired thiol derivative of general formula VIa or Vib.
Exemplary methods for the preparation of compounds having the general Formula Z, as described hereinabove, wherein E represents a sulfoxide linking moiety (xe2x80x94S(O)xe2x80x94) or a sulfone linking moiety (xe2x80x94S(O)2xe2x80x94), are shown in reaction Scheme IV. 
In step A, the resulting thioether derivatives produced, for example, as described in Reaction Scheme I or II (compounds IVa or IVb), may be oxidized to their corresponding sulfoxides (compounds VIIIa or VIIIb) using about one to about five equivalents of a suitable oxidant, such as, for example, hydrogen peroxide or a hydrogen peroxide derivative such as tert-butyl hydroperoxide, peracids (such as 3-chloroperbenzoic acid), halogen oxide derivatives (such as sodium metaperiodate), N-halogenated derivatives (such as N-bromo or N-chlorosuccidimide), and the like (for a review see Madesclaire, M., Tetrahedron 42:5459 (1985)). Presently preferred oxidant for use in the practice of the present invention is about three equivalents of hydrogen peroxide. The above-described reaction is typically carried out in a solvent such as methylene chloride, acetic acid, dioxane, ethanol, methanol, and the like. Presently preferred solvent for use in the practice of the present invention is acetic acid.
Typically the reaction can be carried out over a wide range of temperatures, typically falling in the range of about xe2x88x9278xc2x0 C. up to reflux. Temperatures in the range of about 22xc2x0 C. are presently preferred. Reaction times required to effect the desired oxidation reaction can vary widely, typically falling in the range of 10 minutes up to about 24 hours. Preferred reaction times fall in the range of about 30 minutes to one hour. The resulting sulfoxides (compound VIIIa or VIIIb) may be purified and analyzed by techniques well known to those skilled in the art.
Alternatively, in step B of Reaction Scheme IV, the thioether derivatives (compounds IVa or IVb) may be oxidized to their corresponding sulfones (compounds IXa or IXb) using procedures similar to those described above for preparing sulfoxides, but employing elevated levels of oxidant and/or elevated reaction temperatures. In the present invention, hydrogen peroxide in acetic acid under reflux is the preferred condition (R. Gaul et al., J. Org. Chem. 26:5103 (1961)). The resulting sulfones (compounds IXa or IXb) are purified and analyzed by techniques well known to those skilled in the art.
Exemplary methods for the preparation of compounds having the general Formula Z, as described hereinabove, wherein E is represents an ester linking moiety (i.e., xe2x80x94C(O)Oxe2x80x94), are shown in Reaction Schemes V and VI. In Reaction Scheme V, compounds of Formula X, wherein D is absent or selected from methylene or ethylene, are commercially available and are well known to those skilled in the art. Those compounds not currently available may readily be prepared from starting materials well-known to those skilled in the art. 
In Reaction Scheme V, the aryl acid chlorides of Formula X are effectively contacted with the primary alcohol compounds of Formula IIIa or IIIb, optionally bearing G, and a base such as dimethylaminopyridine (DMAP) under anhydrous conditions in an aprotic solvent, such as, for example, methylene chloride (CH2Cl2), tetrahydrofuran (THF), diethyl ether, benzene, toluene, and the like. Compounds of Formula IIIa or IIIb are described in Scheme I. Similarly, hydroxy derivatives of dialkylamines can be used instead of compounds of Formula IIIa or IIIb. The reaction mixtures are stirred for 1 to 16 hr, with 4 hours preferred, at reaction temperatures within the range of xe2x88x9278xc2x0 C. up to reflux, with ambient temperatures presently preferred. The resulting esters (Formula XIa or XIb) are typically purified and analyzed by techniques well known to those of skill in the art.
Further, compounds of Formula XIa or XIb may be prepared from aryl carboxylic acid derivatives according to Reaction Scheme VI. 
Carboxylic acid derivatives XII employed in Reaction Scheme VI are commercially available or may readily be prepared from well-known starting materials. Compounds of Formula XII are coupled with compounds of Formula IIIa or IIIb in the presence of triethylamine (TEA), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) in an aprotic solvent such as methylene chloride (CH2Cl2) or chloroform and the like. Similarly, hydroxy derivatives of dialkylamines can be used instead of compounds of Formula IIIa or IIIb. The reaction mixtures are stirred for 8 to 16 hr, with 12 hr preferred, at reaction temperatures within the range of xe2x88x9278xc2x0 C. to reflux, with ambient temperatures presently preferred, to afford compounds XIa or XIb. The resulting esters are typically purified and analyzed by techniques well known to those of skill in the art.
Exemplary methods for the preparation of compounds having the general Formula Z , as described hereinabove, wherein D is present or absent and G is a lower alkenylene, are shown in reaction Scheme VII. 
As illustrated in Reaction Scheme VII, thio derivatives I (see Scheme I) are reacted with diethyl chloromethylphosphonate. The reaction is promoted by a suitable base, such as, for example potassium carbonate, sodium hydroxide, sodium ethoxide, sodium hydride and the like in a suitable solvant such as, methanol, ethanol, DMF.
Presently preferred base for use in the practice of the present invention is potassium carbonate in dimethylformamide (DMF). Typically this reaction may be carried out over a wide range of temperature. Temperatures in the range of 0xc2x0 C. to room temperature are presently preferred. Reaction time required to effect the desired reaction can vary widely, typically falling in the range of 10 minutes up to about 24 hours. In the second step compound XIII reacts with the aldehyde or the ketone XIVa or XIVb under Wittig-Horner olefination conditions, well-known to those skilled in the art, to form the olefin XVa or XVb. Compounds XIVa or XIVb are commercially available (e.g., 8-methyl-8-azabicyclo[3.2.1]octane-3-one, Aldrich Chemical Co.), may be prepared from starting materials well-know to those skilled in the art (e.g., 9-methyl-9-azabicyclo[4.2.1]nonane-2-one; Wiseman, J. et al., J. Org. Chem. 2485:13 (1985); 8-methyl-8-azabicyclo[3.2.1]octane-6-one, Aaron, H. S. et al., J. Heterocycl. Chem. 423:5 (1968)) or may be prepared according to Scheme VIII.
A method for the preparation of compounds of Formula XIV is depicted in Scheme VIII. 
In step A of reaction Scheme VIII, aldehyde XVI is contacted with triethyl phosphonoacetate XVII, via a Wittig-Horner reaction well known to those skilled in the art in order to obtain the unsaturated ester (compound XVIII).
In step B of reaction Scheme VIII the resulting unsaturated ester (compound XVIII) may be reduced to the corresponding saturated ester (compound XIX) using procedures well known to those skilled in the art, such as catalytic hydrogenation using a pressure of hydrogen, a catalyst such as PtO2 and a solvent such as acetic acid, ethanol, methanol, and the like.
In step C of reaction Scheme VIII the saturated ester (compound XIX) is contacted with N-methoxy-N-methylamine in the presence of trimethylaluminium in an aprotic solvent such as benzene in order to form the corresponding Weinreb amide (compound XX) (Levin et al., Synt. Com. 12:989 (1982)). Alternatively the ester (compound XIX) can be transformed to the corresponding acyl chloride and transformed to the Weinred amide using condition well known to those skilled in the art (Weinred et al. Tetrahedron Lett 22:3815 (19871)).
In step D of reaction Scheme VIII compound XX may be reduced to the aldehyde (compound XXI) using procedures well know to those skilled in the art, such as lithium aluminium hydride in ether or tetrahydrofuran (THF).
Similarly, aldehyde derivatives of dialkylamines or azabicycloalkanes can be synthesized using the same type of methodology.
Exemplary methods for the preparation of compounds having the general Formula Z, as described hereinabove, wherein E is not present, are shown in Reaction Scheme IX. 
As illustrated in Reaction Scheme IX, halogenated derivatives (compounds XXII), are reacted with diethyl phosphite in an aprotic solvent such as benzene, toluene, acetonitrile, tetrahydrofuran and the like in the presence of a base such as, sodium hydride, butyl lithium, forming the corresponding Wittig-Horner reagent (compounds XXIII). Typically this reaction may be carried out over a wide range of temperatures. Temperatures in the range of about 0xc2x0 C. are presently preferred. Reaction times required to effect the desired coupling reaction can vary widely, typically falling in the range of 10 minutes up to about 24 hours. Preferred reaction times fall in the range of 1 hour. The resulting compounds may be purified and analyzed by techniques well known to those skilled in the art.
In Step B of Reaction Scheme IX, the Wittig-Horner reagent (compounds XXIII) are alternatively contacted with an appropriate aldehyde or ketone (compounds XIVa or XIVb; see Scheme VII), via a Wittig-Horner reaction well-known to those skilled in the art to afford compounds XXIVa or XXIVb.
In Step C of Reaction Scheme XIV, the resulting alkenylene-linker derivatives (compounds XXIVa or XXIVb) may be reduced to their corresponding saturated alkylene derivatives (compounds XXVa or XXVb) using procedures well known to those of skill in the art, such as exposure to hydrogen using a Pd/C catalyst.
Similiary derivatives of dialkylamines can be synthesized using the same type of methodology.
Exemplary methods for the preparation of compounds having the general formula Z, as described hereinabove, wherein E is represents an oxygen linking moiety are shown in Reaction Scheme X. 
In Reaction Scheme X hydroxypyridine derivatives (compound XXVI) are commercially available (e.g., 2-hydroxypyridine, 4-hydroxypyridine, Aldrich Chemical Co.). Compounds of Formula IIIa and IIIb are described in Scheme I. Mitsunobu""s conditions can be used to obtain the desired compound. This reaction is promoted by diethyl azodicarboxylate or diisopropyl azodicarboxylate in the presence of a phosphine such as triphenylphosphine, tributylphosphine and the like. Presently diethyl azodicarboxylate and triphenylphosphine are preferred. The above-described reaction is typically carried out in an aprotic solvent such as tetrahydrofuran(THF), ether, benzene, toluene, acetonitrile and the like. Presently preferred solvent for the use in the practice of the present invention is tetrahydrofuran(THF). Typically the reaction can be carried out over a wide range of temperatures, usually in the range of about xe2x88x9278xc2x0 C., up to reflux. Temperatures in the range of 22xc2x0 C., are presently preferred. The resulting ether (compounds XXVIIa and XVIIb) may be purified and analyzed by techniques well known to those skilled in the art.
In accordance with another embodiment of the present invention, there are provided pharmaceutical compositions comprising substituted pyridine compounds as described above, in combination with pharmaceutically acceptable carriers. Optionally, invention compounds can be converted into non-toxic acid addition salts, depending on the substituents thereon. Thus, the above-described compounds (optionally in combination with pharmaceutically acceptable carriers) can be used in the manufacture of a medicament for modulating the activity of acetylcholine receptors.
Pharmaceutically acceptable carriers contemplated for use in the practice of the present invention include carriers suitable for oral, intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, inhalation, and the like administration. Administration in the form of creams, lotions, tablets, dispersible powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensions or emulsions, patches, and the like, is contemplated. Also contemplated is single dose administration, sustained release administration (e.g., employing time release formulations, metered delivery, repetitive administration, continuous delivery, and the like), administration in combination with other active ingredients, and the like.
For the preparation of oral liquids, suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like.
For the preparation of fluids for parenteral administration, suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
Invention compounds can optionally be converted into non-toxic acid addition salts. Such salts are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, methanesulfonate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate, and the like. Such salts can readily be prepared employing methods well known in the art.